Clinical Nutrition 33 (2014) 737e748

Contents lists available at ScienceDirect

Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

ESPEN endorsed recommendation

Muscle contractile and metabolic dysfunction is a common feature of

sarcopenia of aging and chronic diseases: From sarcopenic obesity to
cachexiaq
Gianni Biolo a, d, f, Tommy Cederholm b, e, Maurizio Muscaritoli c, *, d, f
a
Department of Medical, Surgical and Health Sciences, Clinica Medica, AOUTS, University of Trieste, Italy
b
Clinical Nutrition and Metabolism, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
c
Department of Clinical Medicine, Sapienza e University of Rome, Italy

a r t i c l e i n f o s u m m a r y

Article history: Skeletal muscle is the most abundant body tissue accounting for many physiological functions. However,
Received 25 October 2013 muscle mass and functions are not routinely assessed. Sarcopenia is defined as skeletal muscle loss and
Accepted 24 March 2014 dysfunction in aging and chronic diseases. Inactivity, inflammation, age-related factors, anorexia and
unbalanced nutrition affect changes in skeletal muscle. Mechanisms are difficult to distinguish in indi-
Keywords: vidual subjects due to the multifactorial character of the condition. Sarcopenia includes both muscle loss
Sarcopenia
and dysfunction which induce contractile impairment and metabolic and endocrine abnormalities,
Cachexia
affecting whole-body metabolism and immune/inflammatory response. There are different metabolic
Sarcopenic obesity
Muscle metabolic dysfunction
trajectories for muscle loss versus fat changes in aging and chronic diseases. Appetite regulation and
Pre-cachexia physical activity affect energy balance and changes in body fat mass. Appetite regulation by inflamma-
Muscle contractile dysfunction tory mediators is poorly understood. In some patients, inflammation induces anorexia and fat loss in
combination with sarcopenia. In others, appetite is maintained, despite activation of systemic inflam-
mation, leading to sarcopenia with normal or increased BMI. Inactivity contributes to sarcopenia and
increased fat tissue in aging and diseases. At the end of the metabolic trajectories, cachexia and sarco-
penic obesity are paradigms of the two patient categories. Pre-cachexia and cachexia are observed in
patients with cancer, chronic heart failure or liver cirrhosis. Sarcopenic obesity and sarcopenia with
normal/increased BMI are observed in rheumatoid arthritis, breast cancer patients with adjuvant
chemotherapy and in most of patients with COPD or chronic kidney disease. In these conditions, sar-
copenia is a powerful prognostic factor for morbidity and mortality, independent of BMI.
Ó 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

1. Introduction
A great achievement of modern medicine is the ability to sta-
bilize chronic diseases, leading to extended life expectancy of
populations. The chronically ill patient journey, however, is often
associated with metabolic abnormalities and alterations in body
composition (i.e., muscle loss with changes in adipose tissue mass)
q Joint document endorsed by Special Interest Groups (SIG) “Cachexia-Anorexia
in Chronic Wasting Diseases” and “Nutrition in Geriatrics” of the European Society
of Clinical Nutrition and Metabolism (ESPEN).
* Corresponding author. Department of Clinical Medicine, Sapienza e University
of Rome, Viale dell’Università, 37 00185 Rome, Italy.
E-mail address: maurizio.muscaritoli@uniroma1.it (M. Muscaritoli).
d cancer-related muscle loss.3 Dynapenia defines decreased
ESPEN-SIG “Cachexia-Anorexia in Chronic Wasting Diseases”.
e
ESPEN-SIG “Nutrition in Geriatrics”.
f
These authors equally contributed to conception and writing of the paper.
which affect disease outcome and increase health care burden and
cost. A physiological decline of skeletal muscle tissue is also an
important feature of the aging process. There are strict relation-
ships between muscle loss associated with aging and that due to
chronic diseases. In addition, decreased physical activity and
muscle unloading are key variables affecting skeletal muscle mass
and body composition in aging and chronic disease.
The term sarcopenia was originally introduced to define age-
related skeletal muscle decline, however it is now used to indi-
cate any loss of muscle tissue and function due to aging, chronic
diseases (including cancer), low protein-energy intake and physical
inactivity.1,2 Other definitions may be used to describe decreases in
muscle mass and function. The term wasting describes disease- and
contractility and loss of strength.4 Muscle loss secondary to inac-
tivity and unloading is often referred to as disuse atrophy.5 More

http://dx.doi.org/10.1016/j.clnu.2014.03.007
0261-5614/Ó 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
738 G. Biolo et al. / Clinical Nutrition 33 (2014) 737e748

recently, Fearon et al. proposed the term of “myopenia” to indicate Sarcopenia of aging and chronic diseases: towards a clinical
a clinically relevant degree of muscle loss that is also associated definition and therapy).
with impaired contractile function.6 In 2010 the Special Interest
Groups (SIG) “Cachexia-Anorexia in Chronic Wasting Diseases” and 2. Clinical diagnosis of sarcopenia
“Nutrition in Geriatrics” of the European Society of Clinical Nutri-
tion and Metabolism (ESPEN) defined sarcopenia as any loss of Currently proposed criteria for sarcopenia assessment in a
skeletal muscle mass and strength secondary to aging and chronic clinical setting include determination of muscle mass, strength and
diseases including cancer.1 Subsequently, it was agreed to continue physical performance (Table 1).2,8e17 Muscle mass can be measured
the common efforts aimed at improving the knowledge about by anthropometry,8 bioimpedance analysis (BIA),2,9,13,15 dual en-
sarcopenia, cachexia, pre-cachexia, sarcopenic obesity in aging and ergy X-ray absorptiometry (DXA),11,12 computed tomography (CT)
chronic diseases among the scientific community. The process for scan10,11 and magnetic resonance imaging (MRI). BIA cannot reli-
the production of the present document was started in September ably assess skeletal muscle mass in patients with body fluid ab-
2012 in Barcelona, during the joint meeting of the two ESPEN SIGs. normalities, as liver cirrhosis (LC), chronic kidney disease (CKD),
The draft of the paper was elaborated during the first semester of chronic heart failure (CHF) or cancer.13 Recently, a standardized
2013. The manuscript draft was then circulated among the partic- method has been developed to accurately quantify lumbar skeletal
ipants to the two SIGs (listed in the acknowledgments section in muscle mass in patients using CT images acquired during routine
this paper) and progressively improved and integrated based on the care at the level of the 3rd lumbar vertebra.10,11 This method can be
indications of the participants. The endorsement of the document used only if needed for the underlying disease. For measurement of
by the two SIGs was obtained in September 2013 in Leipzig, during muscle strength the handheld dynamometer is a reliable tool for
the annual joint meeting of the 2 SIGs. In agreement with our measuring strength in upper extremities.15 This method is widely
previous definition,1 in the present paper we will use the term used and has been validated in many physiological and pathological
sarcopenia to define any clinically relevant skeletal muscle loss and conditions. Several tests of physical performance are available such
dysfunction associated with aging, chronic diseases, cancer, low
protein-energy intake and physical inactivity. This definition is also
in agreement with the European Working Group on Sarcopenia in Table 1
Clinical diagnosis of sarcopenia.
Older People (EWGSOP) that in 2010 developed a consensus
document on sarcopenia endorsed by the following organizations: Muscle mass
European Geriatric Medicine Society (EUGMS), the European So- Anthropometry
a
Corrected arm muscle area (CAMA):
21.4 cm2 for men and
21.6 cm2 for
ciety for Clinical Nutrition and Metabolism (ESPEN), the Interna- women
tional Association of Gerontology and GeriatricsdEuropean Region Bioimpedence analysis (BIA)
b
(IAGG-ER) and the International Academy of Nutrition and Aging Fat-free mass index (FFMI):
17 kg/m2 for men;
15 kg/m2 for women.
c
(IANA).2 The EWGSOP made a distinction between aging-associated Skeletal muscle index (SMI): <8.87 kg/m2 for men; <6.42 kg/m2 for women.
Computed tomography scan
sarcopenia (primary sarcopenia) and disease-associated sarcopenia d
Lumbar skeletal muscle index (3rd lumbar vertebra): <55 cm2/m2 for men,
(secondary sarcopenia).2 However, it is difficult to distinguish pri- <39 cm2/m2 for women.
mary from secondary sarcopenia because 90e95% of older adults Dual energy X-ray absorptiometry (DXA)
e
have at least one chronic disease, and 70e75% have two or more Appendicular skeletal muscle index: <7.26 kg/m2 for men; <5.45 kg/m2 for
comorbidities.7 Evidence indicates that chronic diseases prevalence women.
Muscle strength
is increasing over the last decades.7 Handheld dynamometer
In the present joint document elaborated by the ESPEN SIG f
Grip strength (GS, kg) [adjusted for body mass index (BMI, kg/m2)]: Men: BMI
“cachexia-anorexia in chronic wasting diseases” and “nutrition in
24: GS
29; BMI 24.1e28: GS
30; BMI >28: GS
32. Women: BMI
23: GS
geriatrics” we will try to highlight that:
17; BMI 23.1e26: GS
17.3; BMI 26.1e29: GS
18; BMI >29: GS
21.
Physical performance
f
Gait speed (4-m walk test): speed <0.8 m/s
(a) criteria for a clinical diagnosis of sarcopenia are required g
Timed Up and Go (TUG) time that a person takes to rise from a chair, walk
(see: Clinical diagnosis of sarcopenia); three meters, turn around, walk back to the chair, and sit down. >10 s
g
(b) sarcopenia is a key feature of age- and disease-related Short Physical Performance Battery (SPPB) (standing balance, gait speed, and
malnutrition (see: Skeletal muscle as a marker of chair sit-to-stand)
EWGSOP criteria
nutritional status); f
It is required the presence of low muscle mass combined with low strength or
(c) sarcopenia is a multifactorial disorder where specific mech- physical performance, i.e., low SMI by BIA plus low grip strength or low gait
anisms related to aging, chronic disease or inactivity are speed (see above).
difficult to distinguish in individual subjects; in addition, Strength and performance questionnaires
h
SARC-F screen for sarcopenia (0e10 score range) (see Table 1)
sarcopenia includes both muscle loss and muscle dysfunc-
a
tion, the latter not only involves contractile impairment but CAMA is calculated from triceps skinfold thickness (TSF) and mid-upper arm
also metabolic and endocrine abnormalities affecting whole- circumference (MUAC) as follows: MUAC  p  (TSF/10)2)/(4  p]  i. Where i ¼ 10
for men and 6.5 for women. See Ref. 8.
body metabolism, systemic inflammation and immune sys- b
See Ref. 9.
tem regulation (see: Muscle dysfunction: impaired c
Skeletal muscle mass (kg) ¼ [(height2/BIA
contractile, metabolic and endocrine functions); resistance  0.401) þ (gender  3.825) þ (age  0.071)] þ 5.102. Where height is
(d) sarcopenia is a major determinant of disease outcome and measured in centimeters; BIA resistance is measured in ohms; for gender, men ¼ 1
and women ¼ 0; age is measured in years. Absolute skeletal muscle mass (kg) is
longevity (see: Impact of sarcopenia on outcomes);
converted to skeletal muscle index standardizing by meters squared (kg/m2). See
(e) there are different metabolic trajectories for muscle loss European Working Group on Sarcopenia in Older People (EWGSOP) criteria Ref. 2.
versus fat changes in aging and chronic diseases leading to d
See Refs. 10,11. This method can be used only if needed for the underlying
the two different paradigms of sarcopenia, i.e., cachexia and disease.
e
sarcopenic obesity (see: Cachexia and sarcopenic obesity); See Refs. 11,12.
f
See European Working Group on Sarcopenia in Older People (EWGSOP) criteria
and Ref. 2.
(f) cost-effective control of chronic disease and optimal aging g
See Ref. 15.
h
require sarcopenia prevention, diagnosis and treatment (see: See Refs. 16,17.
 G. Biolo et al. / Clinical Nutrition 33 (2014) 737e748 739

as the gait speed, the Timed Up and Go (TUG) and the Short Physical Table 2
Performance Battery (SPPB) which includes standing balance, gait SARC-F screen for sarcopenia.

speed, and chair rises (sit-to-stand).15 Definitions of sarcopenia in Component Question Scoring
individual populations of chronic disease patients are not generally Strength How much difficulty do you have in None ¼ 0
available. Most of the values reported in Table 1 represent lifting and carrying 10 pounds (4.5 kg)? Some ¼ 1
approximately 2 SD below or above mean values for healthy young A lot or
adults, these cut-off values have been used as general provisional unable ¼ 2
Assistance How much difficulty do you have None ¼ 0
references 11,14. These cut-off values, however, could differ ac-
in walking walking across a room? Some ¼ 1
cording to age and ethnicity.12 The EWGSOP proposed a clinical A lot, use aids, or
definition of sarcopenia based on combination of decreased muscle unable ¼ 2
mass and contractile performance (Fig. 1).2 The EWGSOP criteria for Rise from How much difficulty do you have None ¼ 0
a chair transferring from a chair or bed? Some ¼ 1
sarcopenia diagnosis are described in Table 1 and Fig. 1. It is
A lot or
required the presence of low muscle mass by BIA, plus low muscle unable without
strength, or low physical performance; conversely, the presence of help ¼ 2
low muscle mass, normal muscle strength, and physical perfor- Climb stairs How much difficulty do you have None ¼ 0
mance is defined as pre-sarcopenia.2 Volpato et al.18 used the climbing a flight of 10 stairs? Some ¼ 1
A lot or
EWGSOP diagnostic tool for sarcopenia in a large sample of Italian
unable ¼ 2
community-dwelling older adults. Sarcopenia was relatively com- Falls How many times have you fallen in the None ¼ 0
mon only among individuals aged 80 years and older. Prevalence of past year? 1e3 falls ¼ 1
sarcopenia was greater in women (32%) than in men (17%) and was 4 or more
significantly associated to polypharmacy for multiple chronic dis- falls ¼ 2

eases after adjustment for potential confounders.18 Malmstrom & The scores range from 0 to 10, with 0 to 2 points for each component. It is suggested
Morley recently developed the SARC-F questionnaire as a possible that a score equal to or greater than 4 is predictive of sarcopenia and poor outcomes.
See Refs. 16,17.
rapid diagnostic test for sarcopenia based only on muscle con-
tractile performance items.16,17 There were 5 SARC-F components:
strength, assistance with walking, rise from a chair, climb stairs and
muscle, prevalence of muscle depletion was 41% (54% in men and
falls (Table 2). The scores ranged from 0 to 10. A score equal to or
21% in women) in patients with LC listed for liver transplantation.31
greater than 4 was predictive of sarcopenia and poor outcomes.
In patients with non-small cell lung cancer, who were referred
consecutively to a medical oncology service, the prevalence of se-
3. Skeletal muscle as a marker of nutritional status
vere muscle loss was 61% in men and 31% in women despite the fact
that only 3% of men and 12% of women had a BMI lower that
The role of malnutrition in increasing morbidity and mortality in
18.5 kg/m2.24 In stable patients with CHF, treated according to
aging as well as in patients with chronic diseases and cancer has
recent guidelines, the overall prevalence of sarcopenia was about
been long recognized.19,20 The hallmark of disease-related malnu-
20%,27 while the prevalence of cardiac cachexia (defined as unin-
trition is the unintentional loss of body weight secondary to the
tentional non-edematous weight loss of >5% over <6 months) was
variable combination of reduced food intake, impaired substrate
only 10%.28 Muscle loss with relative fat abundance is also common
utilization and increased needs. Indeed, in most observational
among patients with CKD.32 The presence of diabetes mellitus
studies or randomized controlled trials, the assessment of nutri-
accelerated muscle loss in patients with CKD on hemodialysis.33
tional status was mainly based on changes in body weight.21e23
The Korean Sarcopenic Obesity Study detected decreased muscle
However, it is noteworthy that in patients bearing a chronic con-
mass in a large populations of patients with metabolic syndrome or
dition or in the elderly the prevalence of malnutrition is much
type 2 diabetes most of them were overweight or obese.34 For older
greater when definition is based on lean mass and skeletal muscle
adults living in the community or in long-term care facilities, the
rather than on body weight (Table 3).9,24e30 More than 80% of pa-
prevalence of malnutrition according to BMI <18.5 kg/m2 was 2%
tients with chronic obstructive pulmonary disease (COPD) and
and 21%, respectively, while 25% and 33% of them, respectively,
virtually all rheumatoid arthritis (RA) patients have normal or
were sarcopenic according to the definition of EWGSOP.2,30
increased body weight.9,29 Evidence indicates that 20e30% of COPD
patients with normal BMI shows reduced muscle mass according to
dual energy X-ray absorptiometry (DXA) or bio-electrical imped- Table 3
ance analysis (BIA). Using CT scan to quantify lumbar skeletal Prevalence of malnutrition diagnosis based on body mass index or sarcopenia.a

Patient population Malnutrition diagnosis Reference

SLOW Body mass index Sarcopenia
GAIT < 0.8 m/s
SARCOPENIA COPD (male) 10% 20% 9
SPEED1 COPD (female) 18% 27% 9
LOW SMI Lung cancer (male) 3% 61% 24
Lung cancer (female) 12% 31% 24
NORMAL MUSCLE
≥ 0.8 m/s Liver transplantation 15% 37% 25
MASS1 LC (male) 1% 50% 26
NORMAL SMI LC (female) 1% 18% 26
CHF 10% 20% 27,28
GRIP RA (male) 1% 9% 29
LOW
NO SARCOPENIA
STRENGTH1 RA (female) <1% 22% 29
Elderly (community) 2% 25% 30
NORMAL
Elderly (long-term care) 21% 33% 30
a
Sarcopenia is assessed with different methodologies and defined with different
Fig. 1. EWGSOP (European Working Group on Sarcopenia in Older People) criteria terms in references 9,24e30. COPD, chronic obstructive pulmonary disease; LC, liver
to define sarcopenia. 1See Table 1 for definitions. Ref. 2. cirrhosis; CHF, chronic heart failure; RA, rheumatoid arthritis.
740 G. Biolo et al. / Clinical Nutrition 33 (2014) 737e748
Fig. 2. Causes of sarcopenia of aging and chronic diseases (modified from Ref. 1). Sarcopenia of chronic disease can develop at any age. Catabolic factors associated with chronic
diseases (e.g., inflammation, anorexia, insulin resistance, etc.) may accelerate age-related sarcopenia. /, causeeeffect relationships; [, increase; Y, decrease.
4. Muscle dysfunction: impaired contractile, metabolic and
endocrine functions
Skeletal muscle is the largest organ in the human body ac-
counting for about 40e50% of total weight in physiological con-
ditions. Muscle fiber contraction permits locomotion and other
body movements, maintenance of posture, respiration (diaphragm
and intercostal muscles) and communication (verbal and facial
muscles). Skeletal muscle is also involved in a number of meta-
bolic functions such as energy homeostasis, heat regulation, in-
sulin sensitivity and amino acid metabolism. Skeletal muscle has
recently been identified as an endocrine organ. Muscle-derived
cytokines, named myokines, as well as anabolic (e.g., insulin-like
growth factor-1) and catabolic (e.g., myostatin) peptides can be
expressed, produced and released by muscle fibers to exert auto-
crine, paracrine or endocrine actions.35e37 Contraction plays a key
role in regulation of myokine production.35 These peptides
mediate crosstalk between muscle and other tissues, mainly adi-
pose tissue, liver and bone. Their effects include regulation of
systemic inflammation, immune function, energy metabolism,
insulin sensitivity, cell growth, myogenesis, osteogenesis, etc. A
number of factors related to chronic diseases, cancer or aging may
potentially lead to sarcopenia (Fig. 2). We underline the fact that
disease- and age-associated sarcopenia is characterized not only
by decreased muscle mass by also by functional abnormalities
involving the contractile, metabolic and endocrine activities of this
tissue (Fig. 3).
4.1. Mechanisms of sarcopenia
Causes of sarcopenia in chronic diseases and cancer as well as in
aging are summarized in Fig. 2. Key mechanisms include inflam-
mation, inactivity, low-protein intake and age-related factors.
Mechanisms of skeletal muscle aging and their influence on age-
related diseases (e.g., metabolic syndrome, cancer, Alzheimer’s
and Parkinson’s disease) are reviewed in Ref. 38. Sarcopenia is a
multifactorial disorder, i.e., specific mechanisms related to aging,
chronic disease, physical inactivity and low protein-energy intake
are difficult to distinguish in individual subjects.39 Loss of skeletal
muscle occurs exponentially with aging and is influenced by the
level of physical activity.40 Low energy intake also contribute to
skeletal muscle loss in both active41 and inactive42 subjects. Severe
injury or infection is accompanied by both systemic inflammatory
response to stress and prolonged inactivity or bed rest. Inflam-
mation and decreased physical activity are also characteristic fea-
tures of chronic disease and cancer.43 Although bed rest alone can
result in a 3e5% loss of lean body mass in healthy volunteers, the
effects of severe stress combined with muscle unloading can be 2-
to 3-fold greater. The systemic inflammatory response involves
stimulation of a number of mediators (mainly cortisol and pro-
inflammatory cytokines) which can directly activate the ubiq-
uitineproteasome pathway and autophagy in skeletal muscle as
well as inhibit synthesis of myofibrillar proteins. Decreases in
anabolic stimulation by factors such as sex hormones and insulin-
like growth factor-1 as well as glucocorticoid therapy may also
contribute to sarcopenia in selected conditions. Skeletal muscle
responds rapidly to decrease contractile activity.44 Redox imbal-
ance, activation of the major catabolic systems, ubiquitineprotea-
some and autophagy, and decreased protein synthesis may
contribute to the progression of inactivity-related sarcopenia.45
Evidence indicates that inactivity amplifies the catabolic response
of skeletal muscle to inflammatory mediators. In healthy volun-
teers, the muscle catabolic effects of experimental hyper-
cortisolemia, at concentrations that mimic severe injury, were 3-
fold greater during experimental bed rest than in ambulatory
conditions.46 Early physical rehabilitation of the acutely ill patient
and exercise training programs for the patients with chronic dis-
ease or cancer as well as for the elderly has been shown to be
beneficial to preserve muscle mass and improve clinical out-
comes.47e50 Exercise training is particularly effective in the treat-
ment of those chronic patients with glucocorticoid-induced muscle
loss. In physiological aging, sarcopenia prevention through
increased physical activity has been shown to be more effective in
men than in women.40
 G. Biolo et al. / Clinical Nutrition 33 (2014) 737e748 741

CHRONIC AGING
DISEASES

SARCOPENIA
SKELETAL MUSCLE LOSS AND DYSFUNCTION
MASS CONTRACTILE METABOLIC MYOKINE
DEPLETION INSUFFICIENCY IMPAIRMENT DYSREGULATION

Anabolic Altered energy

resistance expenditure
Decreased
Insulin
Glutamine antioxidant
resistance
depletion capacity

MORBIDITY
Dynapenia, fatigue, disability and falls, impaired ventilation, osteoporosis,
bone fractures, dyslipidemia, metabolic syndrome, type 2 diabetes,
increased cardiovascular risk, impaired immunity, infections, etc.

MORTALITY
Fig. 3. Skeletal muscle loss and dysfunction characterize sarcopenia of aging and chronic diseases. Sarcopenia increases morbidity and mortality in aging as well as in cancer,
chronic obstructive pulmonary disease, chronic kidney disease, liver cirrhosis, heart failure, rheumatoid arthritis, HIV infection. /, causeeeffect relationships; [, increase; Y,
decrease.

4.2. Energy expenditure and muscleefat interaction
Skeletal muscle mass is a major determinant of daily energy
expenditure at rest and during physical activity. In physiological
conditions, the metabolic rate of skeletal muscle accounts for about
20% of whole body resting energy expenditure.51 When measured
by indirect calorimetry, resting metabolic rate is strictly propor-
tional to lean body mass. In 6-week experimental bed rest studies
in healthy young volunteers, muscle disuse atrophy was associated
with 38% decrease in energy expenditure for physical activity52 and
with 6% decrease in resting energy expenditure, i.e., about 30e
40 kcal/day for each kg of lean body mass lost throughout the
experimental period.53 Energy expenditure and requirement are
greatly decreased in patients with severe inactivity-related sarco-
penia.54 In patients with muscle wasting, energy requirement,
calculated by equations based on body weight, is constantly over-
estimated.55 Thus, in all conditions of muscle disuse atrophy energy
requirement is decreased due to reductions in both resting and
activity-related energy expenditure. The rate of fat deposition tends
to increase, especially at the abdominal level,56 leading to activa-
tion of systemic inflammation57,58 and insulin resistance.59e61
These alterations enhance the catabolic effect of inactivity.58 This
vicious cycle (Fig. 4), that leads to progressive muscle loss and fat
gain, is frequently observed in some patients with chronic diseases
and cancer as well as in sedentary lifestyle and in aging. In fact, total
energy expenditure decreases substantially in aging resulting from
parallel changes in resting metabolic rate and activity.62 Resting
metabolic rate may be increased in selected chronic diseases.
Amyotrophic lateral sclerosis is characterized by severe disuse at-
rophy, while resting energy expenditure is increased leading to
weight loss and cachexia.63,64 Hypermetabolism may also occur in
sub-groups of stable patients with LC or COPD.65,66 Hypermetabolic
patients suffering from chronic diseases have a poor prognosis. The
origins of such hypermetabolism need to be elucidated.
4.3. Impaired contractility and muscleebone interaction
Although muscle mass determines contraction strength, clear
evidence indicate that the relationship between muscle mass and
contractile function is highly variable. Strength does not decrease
proportionally to muscle mass.67 Decreased contractility leads to
loss of strength (i.e., dynapenia), fatigue, disability and falls,
impaired pulmonary ventilation as well as to osteoporosis and
fractures due to reduced mechanical bone stimulation.4 Dynapenia
is a key determinant of quality of life and an indicator of loss of
independence in chronically ill patients and in the elderly. Muscle
742 G. Biolo et al. / Clinical Nutrition 33 (2014) 737e748
INACTIVITY
SARCOPENIA
DECREASED
INFLAMMATION
ENERGY
INSULIN
EXPENDITURE
RESISTANCE
MUSCLE - FAT
INTERACTION
POSITIVE
FAT MASS
ENERGY
DEPOSITION
BALANCE
Fig. 4. Muscleefat interaction during inactivity. Energy expenditure and require-
ment are greatly decreased in patients with inactivity-mediated sarcopenia. The rate of
fat deposition tends to increase, especially at the abdominal level, leading to activation
of systemic inflammation and insulin resistance. These alterations enhance the cata-
bolic effect of inactivity. This vicious cycle, that leads to progressive muscle loss and fat
gain, is frequently observed in patients with chronic diseases or breast cancer as well
as in aging and sedentary lifestyle.
strength and postural stability are also closely related to the risk of
falls as well as to clinical outcomes. Evidence suggests that a sexual
dimorphism may exist in disease-mediated dynapenia. In 1500
hospitalized patients for acute disease who were progressively
losing weight, male subjects exhibited a larger percentage reduc-
tion in hand grip strength (11%) than women did (4%).68
Epidemiological evidence indicates that sarcopenia, as well as
muscle depletion or dynapenia alone are strictly associated with
osteoporosis.69 In women after the menopause, but also in elderly
men, bone mass progressively declines. As in the elderly, immobi-
lized or bedridden individuals of any age also exhibit decreasing
bone mass.70,71 It is well established that muscle mass and
contraction provide the mechanical load that stimulates bone
anabolism.72 Besides biomechanical function, skeletal muscle is
able to secrete myokines capable of modulating bone biological
functions.72 Nutritional factors may also contribute to bone anab-
olism and catabolism. In addition to the well-known relationship
between muscle and bone loss in aging and physical inactivity,
systemic inflammation can directly induce muscle and bone losses
as seen in most chronic diseases.73e76 DXA is a suitable method-
ology for concomitant assessment of both lean body mass and bone
density.
4.4. Insulin resistance
Skeletal muscle is the major site of dietary glucose disposal;
therefore, muscle sensitivity to insulin action is essential for
the development of whole body insulin resistance and
hyperglycemia.77 Insulin resistance is strictly associated with type 2
diabetes and abdominal obesity. Inflammatory mediators, such as
cortisol and some cytokines, directly cause insulin resistance as
seen in acute and chronic diseases characterized by systemic
inflammation. Defective muscle mass may also contribute to insulin
resistance. A large epidemiological study indicated a significant
inverse association between skeletal muscle mass and insulin
sensitivity as estimated by bioimpedance and homeostatic model
assessment, respectively.78 Muscle insulin resistance rapidly de-
velops following inactivity, before any significant loss of muscle
mass.79 Skeletal muscle insulin resistance directly contributes to
cardiovascular risk through induction of dyslipidemia (i.e.,
decreased HDL cholesterol and increased triglycerides) as shown in
experimental bed rest studies.80 Insulin resistance with fat accu-
mulation contributes to a lesser post-prandial protein anabolism in
skeletal muscle.59e61,81
4.5. Anabolic resistance
In physiological conditions, skeletal muscle is characterized by
net protein catabolism in the fasting state, while in the post-
prandial state dietary amino acids and endogenous insulin
interact to stimulate muscle protein synthesis and prevent loss of
muscle mass throughout the day. In aging and inactivity as well as
in a number of chronic and acute diseases, the ability of amino
acids to stimulate protein synthesis in skeletal muscle is
reduced.82e84 This abnormality, defined as anabolic resistance, can
be at least in part counteracted by increasing physical activity and
dietary protein intake.83,84 Abnormalities in dietary amino acid
handling by the intestinal mucosa may contribute to post-prandial
amino acid availability to skeletal muscle in aging and disease
states.85
4.6. Amino acid release and glutamine production
In catabolic conditions and in the fasting state skeletal muscle
releases free amino acids86 to support protein synthesis in other
tissues such as liver, immune cells and intestinal mucosa. In
anabolic conditions amino acids are taken up by skeletal muscle. In
contrast to the other amino acids, the non-essential amino acid
glutamine is largely de-novo synthesized and stored in skeletal
muscle.87 Glutamine is continuously released from muscle to pro-
vide energy substrate and precursor for nucleic acid synthesis to
the rapidly dividing cells of the immune system and the intestinal
mucosa.87 During stress conditions, peripheral glutamine require-
ment is increased while skeletal muscle is relatively inefficient to
provide enough glutamine to the whole body. Muscle and systemic
glutamine depletion in injuries and sepsis has been associated with
increased morbidity and mortality. Physical exercise increases
muscle glutamine production while inactivity decreases glutamine
availability.88
4.7. Decreased antioxidant capacity
Antioxidant systems in skeletal muscle play a key role in
counteracting exercise-mediated production of reactive oxidant
species. In addition, antioxidant capacity of skeletal muscle con-
tributes to reduction of whole body oxidative stress in physiological
and pathological conditions.89,90 Exercise training results in an
elevation in the activities of both superoxide dismutase and
glutathione peroxidase along with increased cellular concentra-
tions of glutathione in skeletal muscles. In contrast, inactivity leads
to redox unbalance both in skeletal muscle91 and at the systemic
level.58
 G. Biolo et al. / Clinical Nutrition 33 (2014) 737e748 743

4.8. Myokine dysregulation increased risk of non-alcoholic fatty liver disease.119 In alcoholics,
loss of lean mass is associated with worse outcome while there is
The first identified myokine is interleukin-6 (IL-6) which in- no association between changes in fat parameters and mortality.99
creases up to 100-fold in the circulation during exercise and de- In CKD patients on peritoneal dialysis, lean body mass is a reliable
clines in the post exercise period. Many additional signaling predictor of long-term survival.100 In COPD patients, the clinical
molecules have been recently identified to be produced by con- outcome is affected more by changes in lean body than in total body
tracting myofibers such as IL-8, IL-15, brain-derived neurotrophic mass.101e103 Such association between sarcopenia and outcome in
factor, leukemia inhibitory factor, follistatin-like 1, fibroblast COPD was more pronounced in women.103 In cancer,
growth factor-21, irisin etc. Evidence suggests that muscle-derived chemotherapy-related toxicity and side effects are more prevalent
myokines contribute to the beneficial effects of exercise including in muscle-depleted patients104,105 and muscle mass appears to
decreased systemic inflammation and improved insulin sensitivity. predict the risk of toxicity better than body surface area.105 In
In contrast, muscle disuse atrophy and aging are associated with addition, muscle loss is associated with worse patient survival
upregulation of muscle expression of pro-inflammatory cytokines following cancer surgery.106,107 Therefore, the view is consolidating
and catabolic myokines such as myostatin.92,93 Muscle IL-6 that loss of muscle mass should be regarded to as the major
expression appears important for the initial growth response dur- responsible for the negative outcomes of disease-related malnu-
ing the recovery from disuse.94 The systemic stress response in- trition, including loss of autonomy and impaired quality of life. In
cludes enhanced expression of pro-inflammatory myokines in longitudinal studies, sarcopenia has been indicated as a reliable
skeletal muscle.95 Irisin is a recently described myokine to be independent predictor of all-cause mortality also among the
secreted by skeletal muscle upon exercise.96 It has been proposed elderly, irrespective of fat mass.108,109 Sarcopenic as compared to
to promote the browning of white adipose tissue that results in non sarcopenic elderly individuals have a three-time greater risk of
enhanced thermogenesis and increased energy expenditure. Irisin falls.110 Sarcopenia and malnutrition impose a significant economic
levels has been also found to be associated with insulin resistance burden on healthcare services.120e122 In addition to muscle mass,
and cardiometabolic risk variables suggesting a compensatory in- also muscle strength and physical performance were associated to
crease of this peptide to overcome an underlying irisin resistance in mortality in CKD,111 CHF112,113 or COPD114 as well as in surgical
metabolic syndrome.97 It may be speculated that major irisin ef- patients115 and in the elderly.116,117 Muscle strength and perfor-
fects are yet to be uncovered. mance are better prognostic factors then muscle mass when all
variables are included in predictive equations.4
5. Impact of sarcopenia on outcomes
6. Cachexia and sarcopenic obesity
Recent epidemiological evidence suggests that the harmful ef-
fect of low BMI on outcomes is largely due to the deleterious effects While impaired energy balance mainly affects adipose tissue
of muscle loss and dysfunction (Table 4).14,26,98e117 A number of and fat mass, inflammation, catabolic hormones, inactivity and
epidemiological evidence indicates muscle depletion as reliable insufficient protein intake are the main drivers of sarcopenia of
marker of poor prognosis in chronic diseases. Muscle loss is aging and chronic diseases (Fig. 5).123 We have recently defined
frequently found in end-stage liver disease,118 in these patients cachexia and pre-cachexia as conditions characterized by actual or
sarcopenia increased the risk of hepatic encephalopathy98 and was potential unintentional weight loss associated with systemic
independently associated with mortality while it did not correlate inflammation.1,124 In these conditions, systemic inflammation is
with the degree of liver dysfunction evaluated by using the model associated with anorexia and low nutrient intake, in turn leading to
for end-stage liver disease (MELD) and the Child-Pugh scoring accelerated losses of both skeletal muscle and fat tissue. Pre-
systems.26 In addition, individuals with lower muscle mass exhibit cachexia should be promptly identified and nutritional interven-
tion should be early implemented to prevent progression to
cachexia with its life-threatening sequelae.125e127 In addition to
Table 4 disease-related anorexia, polypharmacy, maldigestion, malab-
Impact of sarcopenia on clinical outcomes. sorption, dysphagia and other eating disabilities may contribute to
Muscle Patient population Outcomes Reference decreased energy intake.128 Quite interestingly, however, in
abnormality selected inflammatory states the cytokine and hormonal milieu is
Muscle lossa LC [ hepatic 98
not associated with impaired appetite. These conditions are char-
encephalopathy acterized by sarcopenia with normal or even increased fat mass.
Muscle loss LC [ mortality 26 Rheumatoid arthritis (RA), a chronic inflammatory disease in which
Muscle loss Alcohol addiction [ mortality 99 inflammatory cytokines have a central role in the pathogenesis is
Muscle loss CKD e peritoneal [ mortality 100
probably the best paradigm of such clinical conditions. Besides joint
dialysis
Muscle loss COPD [ mortality 101e103 symptoms, systemic features, such as loss of body protein, partic-
Muscle loss Cancer [ chemotherapy- 104,105 ularly in skeletal muscle mass (leading to sarcopenia) but also in
related toxicity the immune system and the viscera, muscle weakness, insulin
Muscle loss Cancer [ mortality 14 resistance, fatigue and impaired adaptation to metabolic stress,
Muscle loss Cancer surgery [ mortality 106,107
Muscle loss Elderly [ mortality 108,109
negatively affect morbidity and mortality in RA patients.129 Thus,
Muscle loss Elderly [ risk of falls 110 sarcopenia in RA patients is associated with poor clinical outcome,
Dynapeniaa CKD [ mortality 111 despite normal or even increased body weight. The term “rheu-
Dynapenia CHF [ mortality 112,113 matoid cachexia” has been used to define the loss of fat-free mass,
Dynapenia COPD [ mortality 114
predominantly skeletal muscle, that occurs in RA in the presence of
Dynapenia Surgery [ mortality 115
Dynapenia Elderly [ mortality 116,117 stable or increased fat mass.129 Loss of body weight does not always
a
occur, which makes this form of cachexia often underestimated, but
Muscle loss and dynapenia are assessed with different methodologies and
defined with different terms in references 14,26,98e117. LC, liver cirrhosis; CKD,
also substantially different from the ‘classic’ cachexia of chronic
chronic kidney disease; COPD, chronic obstructive pulmonary disease; CHF, chronic diseases, in which unintentional weight loss and/or low BMI values
heart failure. represent a hallmark for diagnosis.1,124 Conversely, at the same
744 G. Biolo et al. / Clinical Nutrition 33 (2014) 737e748

Fig. 5. Metabolic trajectories of sarcopenia of aging and chronic diseases. Inactivity, inflammation and anorexia as well as age-related catabolic factors are the major metabolic
variables affecting changes in body composition. Inactivity, inflammation and aging are the key mechanisms leading to sarcopenia. Inactivity with no anorexia is associated with
decreased energy expenditure and fat mass accumulation. Energy expenditure is further decreased in sarcopenia. Sarcopenic obesity is defined by the association of sarcopenia and
fat deposition. The association of anorexia and inflammation leads rapidly to parallel losses of fat and skeletal muscle. This condition is clinically defined as cachexia. Pre-cachexia is
characterized by anorexia and systemic inflammation with no or limited weight loss. A pre-cachectic patient should be nutritionally supported to prevent cachexia that is usually an
irreversible condition. Sarcopenia (i.e., skeletal muscle loss and dysfunction) is common feature of both sarcopenic obesity and cachexia. Cachexia, sarcopenic obesity or muscle loss
with normal or increased BMI may be observed in any chronic disease. Nonetheless, sarcopenic obesity or muscle loss with normal or increased BMI are usually observed in
rheumatoid arthritis, breast cancer patients with adjuvant chemotherapy and in most of patients with COPD or chronic kidney failure. Cachexia is usually observed in patients with
advanced cancer, congestive heart failure or liver cirrhosis. Not only cachexia and sarcopenic obesity but also muscle loss and dysfunction with normal or increased BMI is associated
with increased morbidity and mortality. /, causeeeffect relationships; [, increase; Y, decrease.

weight and BMI, patients with RA have significantly lower fat-free disease and type-2 diabetes, obese people with chronic diseases,
mass and insulin sensitivity compared to the normal population.129 such as COPD, CKD and CHF as well as those admitted to intensive
Besides, it has been consistently demonstrated that dietary intake care unit, have a better chance of survival than normal-weight in-
is not different between patients with RA and healthy controls,129 dividuals.135e138 It is well known that adult obese subjects without
indicating that anorexia and reduced food intake (which charac-
terize pre-cachexia and cachexia of chronic diseases) are uncom-
mon features in RA.
In a recent paper, van Bokhorst-de van der Schueren et al.29
confirms that RA is the paradigm of sarcopenia associated with
normal or increased fat mass. This condition cannot be defined as
pre-cachexia because is not associated with anorexia and reduced
food intake and, therefore, does not require nutritional supple-
mentation. Sarcopenia with normal or increased body fat is not
only observed in RA, but also in breast cancer patients treated with
adjuvant chemotherapy130 and in most of patients with CKD131 or
COPD.9 Muscle loss and dysfunction associated with pathological
accumulation of adipose tissue is defined as sarcopenic obesity.132
This condition may be associated with the cumulative risk
derived from sarcopenia and dysfunction and obesity. The clinical
outcome of sarcopenic obese patients with chronic diseases or
cancer is worse than that of obese patients with normal muscle
mass.133,134 Two different trajectories may lead to sarcopenic
obesity132 (Fig. 6). First, long-term physical inactivity combined
with positive energy balance (secondary to overfeeding and low
energy requirement) may progressively lead to obesity with disuse Fig. 6. Metabolic trajectories of sarcopenic obesity. Two hypothetical metabolic
trajectories may lead to the same sarcopenic obese phenotype. First, long-term
muscle atrophy in otherwise healthy individuals, according to the
physical inactivity combined with positive energy balance (secondary to overfeeding
mechanism described in Fig. 4. Second, in obese patients bearing a and low energy requirement) may progressively lead to obesity with disuse muscle
chronic comorbidity (e.g., COPD, RA, CKD or CHF), the activation of atrophy an otherwise healthy individual with normal BMI, according to the mechanism
systemic inflammation may rapidly lead to muscle loss and described in Fig. 4. Second, a chronic disease with activation of systemic inflammation
dysfunction and sarcopenic obesity (see Fig. 5). may rapidly bring an otherwise healthy obese individual to Muscle loss and
dysfunction and sarcopenic obesity (see also Fig. 5). Energy intake and requirement
The association between skeletal muscle mass and better could be in parallel reduced leading to fat mass preservation. Obese individuals
outcome in obesity may also contribute to explain the so called without established comorbidities are often characterized by an increased fat-free
“obesity paradox”. While obesity is a risk factor for cardiovascular mass index (FFMI) as compared to subjects with normal BMI.
 G. Biolo et al. / Clinical Nutrition 33 (2014) 737e748
established comorbidities are usually characterized by larger skel-
etal muscle mass as compared to those with normal BMI, due to the
anabolic effect induced by their heavier body weight139 (Fig. 6).
Recent studies suggest that a considerable proportion of the obesity
paradox might be explained by the amount of skeletal muscle mass
and by the rates of its decline in the different chronically ill obese
patients140e142 (Fig. 6).
7. Sarcopenia of aging and chronic diseases: towards a clinical
definition and therapy
It is becoming increasingly clear that the spectrum of body
composition changes in chronic diseases and aging is extremely
wide, ranging from the minimal or potential weight loss of pre-
cachexia to the extreme loss of fat and muscle in refractory can-
cer cachexia,11 to the high BMI of sarcopenic obesity. Nonetheless,
sarcopenia with muscle loss and dysfunction is a common feature
of virtually all chronic diseases characterized by inactivity and
systemic inflammation as well as of aging. Reliable diagnostic tools
and biomarkers for identifying sarcopenia, which includes muscle
loss and dysfunction, in patient populations are required for clinical
practice. Appetite regulation and the level of physical activity are
the major determinants of energy balance and of changes in body
fat mass. Mechanisms of appetite regulation by inflammatory
mediators are poorly understood. In some patients, inflammation
leads to anorexia and loss of fat in combination with sarcopenia. In
others, appetite and food intake are maintained, despite activation
of systemic inflammation, leading to the association of sarcopenia
with normal or increased BMI. Inactivity further contributes to
sarcopenia, with muscle loss and dysfunction, and to increased fat
tissue. Cachexia and sarcopenic obesity are paradigms of the two
patient categories. The wide phenotypic variability of patient body
composition, even within the same disease, requires careful
tailoring of energy and protein prescription. Nutritional in-
terventions in muscle-depleted patients with increased fat mass
should involve careful assessments of energy requirement to pre-
vent further increases in adipose tissue. In fact, overfeeding accel-
erated muscle loss and activated systemic inflammation in
bedridden subjects.58 Protein intake should be increased in order to
counteract the anabolic resistance associated with inflammation
and inactivity.143 The PROT-AGE study group has recently recom-
mended an average daily intake in the range of 1.0e1.2 g protein/kg
body weight/day for healthy older people (>65 years). Older pa-
tients who have acute or chronic diseases need even more dietary
protein, i.e., 1.2e1.5 g/kg body weight/day.84 Both endurance and
resistance-type exercises are recommended in muscle-depleted
patients with increased fat mass to maintain skeletal muscle
mass and functions as well as energy balance. Energy restriction
programs in inactive patients would accelerate muscle loss.42 Evi-
dence indicates that restrictive diets impose significant risks of
sarcopenia and malnutrition in free-living elderly population.144
8. Conclusions
The spectrum of body composition changes in disease states is
extremely wide, ranging from the minimal or potential weight loss
of pre-cachexia to the extreme loss of fat and muscle in refractory
cancer cachexia, to the high BMI of sarcopenic obesity. During the
last few years, the progressive understanding of the pathophysi-
ology and clinical impact of disease-related changes in body
composition, has highlighted the central role played by skeletal
muscle loss in negatively influencing morbidity and mortality in
acutely and chronically ill patients. Skeletal muscle is the most
abundant tissue in the body and, besides contraction, it is respon-
sible for metabolic and endocrine/paracrine functions, including
745
production and secretion of anabolic and catabolic peptides,
modulation of insulin resistance, systemic inflammation and en-
ergy expenditure, cross-talking with bone mass, etc. Muscle loss
implies variable degrees of dysfunction of such complex machinery,
which will in turn variably affect quality of life, autonomy, perfor-
mance, tolerance to treatments and survival of chronically ill
patients.
Sarcopenia, which includes muscle loss and dysfunction, is a
common feature of virtually all chronic diseases with inflammation
and involves impairment of either contractile, metabolic and
endocrine functions of skeletal muscle. Early identification of sar-
copenia would allow for timely appropriated preventative and
therapeutic interventions for this clinical entity. For the time being,
currently available tools for assessment of muscle mass and
strength should be implemented as much as possible in clinical
practice.145 In the future, sarcopenia diagnosis could rely not solely
on assessment of muscle mass and strength, but also on identifi-
cation of metabolic and endocrine alterations. Evidence indicates
that, while sarcopenia may rapidly develop, its correction may
represent a long-term process. This may explain why a high num-
ber of clinical studies failed to show significant benefits of nutri-
tional interventions on outcomes and underscore the need of
adequate prevention of sarcopenia in clinical practice. Future
studies should concentrate on metabolic interventions aiming at
sarcopenia as specific target.
Conflict of interest
The Authors declare they have no conflict of interest.
Acknowledgments
We thank all members of the Special Interest Groups (SIG)
“Cachexia-Anorexia in Chronic Wasting Diseases” and “Nutrition in
Geriatrics” of the European Society of Clinical Nutrition and
Metabolism (ESPEN). We acknowledge the contribution of the
following SIG members for critical revision of the manuscript:
Stefan Anker, Charité, Campus Virchow, Klinikum, Berlin, Germany;
Didier Attaix, INRA de Theix, Ceyrat, France; Vickie Baracos, Uni-
versity of Alberta, Edmonton, Alberta, Canada; Juergen Bauer,
Friedrich Alexander University, Erlangen, Nürnberg, Germany; Yves
Boirie, Université d’Auvergne, Clermont-Ferrand, France; Marian
Bokhorst e de van der Schueren, VU University Medical Center,
Amsterdam, The Netherlands; Federico Bozzetti, Italy; Paola Cost-
elli, University of Turin, Turin, Italy; Alfonso J. Cruz Jentoft, Hospital
Universitario Ramon y Cajal, Madrid, Spain; Maria Pía de la Maza
University of Chile, Santiago, Chile; Jean-Claude Desport, University
Hospital Limoges, France; Yosef Dror, Hebrew University, Rehovot,
Israel; Ken Fearon, Edinburgh University, Edinburgh, UK; Alastair
Forbes University College London e London UK; M. Cristina Gon-
zalez, Universidade Católica de Pelotas, RS, Brasil and Pennington
Biomedical Research Center, Baton Rouge, LA, USA; Robert F.
Grimble, University of Southampton, Southampton, UK; Harriët
Jager-Wittenaar, University Medical Center Groningen, Groningen,
The Netherlands; Alessandro Laviano, Sapienza University of Rome,
Rome, Italy; Olle Ljungqvist, Örebro University Hospital, Örebro,
Sweden; Marcello Maggio, University of Parma, Parma, Italy;
Alberto Mijan-de-la-Torre Burgos University Hospital, Valladolid,-
Spain; Claude Pichard, Geneva University Hospital, Geneva,
Switzerland; Filippo Rossi Fanelli, Sapienza University of Rome,
Rome, Italy; Cornel Sieber, Friedrich Alexander University, Erlan-
gen, Nürnberg, Germany; Schneider Stèphane University of Nice-
Sophia Antipolis, Nice, France; Florian Strasser, Cantonal Hospital,
St. Gallen, Switzerland; Jean-Paul Thissen, Université Catholique de
Louvain, Bruxelles, Belgium; Paul Van Leeuwen, VU University
746 G. Biolo et al. / Clinical Nutrition 33 (2014) 737e748
Medical Center, Amsterdam, The Netherlands; Stephan Von Haeling
Charité Universitätsmedizin Berlin e Berlin, Germany; Dan Waitz-
berg University of São Paulo Medical School e São Paulo, Brazil.
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